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Their involvement spans from acute traumatic brain injury to chronic neurodegenerative diseases, in which they participate in pathological regulation through mechanisms such as homeostatic disruption, oxidative stress, induction of specific cell death pathways, thereby influencing secondary neuronal death and impaired regeneration. This review summarizes the pathophysiological roles of metal ions and their associations with acquired brain injury and neurodegenerative diseases, aiming to further elucidate targetable therapeutic windows for neuroprotection and neural repair. Furthermore, we evaluate the translational challenges of clinical-stage metal chelators (e.g., deferiprone, PBT2) and highlight novel nano-delivery strategies designed to cross the blood-brain barrier to reverse subcellular metal toxicity. This provides a clear therapeutic roadmap for developing next-generation neuroprotective drugs.<\/jats:p>","DOI":"10.3389\/fphar.2026.1916973","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T05:31:45Z","timestamp":1785994305000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Metal ion dyshomeostasis in neurological disorders: from pathological mechanisms to targeted neuroprotective and regenerative strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"Mengqiang","family":"Yao","sequence":"first","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University","place":["Shanghai, China"]},{"name":"School of Medicine, Shanghai University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlei","family":"Xing","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University","place":["Shanghai, China"]},{"name":"School of Medicine, Shanghai University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University","place":["Shanghai, China"]},{"name":"School of Medicine, Shanghai University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochen","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University","place":["Shanghai, China"]},{"name":"School of Medicine, Shanghai University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingji","family":"You","sequence":"additional","affiliation":[{"name":"School of Medicine, Shanghai University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Su","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.neuron.2008.06.018","article-title":"Rapid restoration of cognition in Alzheimer\u2019s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial A\u03b2","volume":"59","author":"Adlard","year":"2008","journal-title":"Neuron"},{"key":"B2","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.freeradbiomed.2018.04.002","article-title":"Brain mitochondrial iron accumulates in Huntington\u2019s disease, mediates mitochondrial dysfunction, and can be removed pharmacologically","volume":"120","author":"Agrawal","year":"2018","journal-title":"Free Radic. 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